Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans

Abstract

Background: Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European-descent individuals. Yet population-specific genetic variation can occur, and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined cross-cancer pleiotropic associations with lung cancer risk in African Americans. Methods: We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status. Results: We identified three novel genomic regions significantly associated (FDR-corrected P <0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with reduced risk [OR ¼ 0.43; 95% confidence interval (CI), 0.73-0.89], and functional annotation using GTEx showed rs7186207 modifies DHODH gene expression. The minor allele at rs336958 on 5q14.3 was associated with increased lung cancer risk (OR ¼ 1.47; 95% CI, 1.22-1.78), whereas the minor allele at rs11658063 on 17q12 was associated with reduced risk (OR ¼ 0.80; 95% CI, 0.72-0.90). Conclusions: We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain HNF1B, DHODH, and HAPLN1 genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans. Impact: Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.

Metformin, an AMPK Activator, Inhibits Activation of FLSs but Promotes HAPLN1 Secretion

“…54 HAPLN1 is also a susceptibility gene for lung cancer. 55 In RA, Urano et al 56 studied the correlation between HAPLN1 gene polymorphism and spinal degenerative changes in 622 post-menopausal Japanese women and showed that mutations in the specific HAPLN1 loci are related to spinal degeneration. Furthermore, genome-wide association analysis reported HAPLN1 as one of the important susceptibility genes for ankylosing spondylitis in the Han population.…”

Cross-cancer evaluation of polygenic risk scores for 16 cancer types in two large cohorts

“…Genome-wide association studies (GWAS) of individual cancer types have also identified loci associated with multiple cancer types, including 5p15 ( TERT-CLPTM1L) 3 , 6p21 (HLA complex) 4 , 5 , and 8q24 6 . Non-GWAS approaches have yielded further pleiotropic cancer risk variants 7 – 27 , and genetic correlation studies have identified cancer pairs with shared heritability 28 – 31 .…”

Haplotypes of single cancer driver genes and their local ancestry in a highly admixed long-lived population of Northeast Brazil

“…, 2015 ; Ríos-Tamayo et al , 2016 ; Oh et al, 2017a ; Tong et al., 2018 ) rs11651052 ( Painter et al , 2015 ). Endometrial cancer risk rs11658063 ( Jones et al, 2019 ) CAG (10.8%) -0.95 72.4 0.606 0.9-0.98 TA C (31.5%) -0.96 79.96 0.688 0.92-0.99 TAG (6,8%) -0.95 51.56 0.453 0.89-0.99 BRCA1 TG (69.2%) rs16942 rs1799949 -0.99 101.43 0.868 0.96-1.0 rs16942 ( Cox et al , 2011 ; Heramb et al. , 2015 ; Sagna et al, 2019 ) rs1799949 ( Ricks-Santi et al , 2017 ).…”

“…The present study was based on 35 SNPs that can potentially modify the risk of cancer. A literature research revealed that only 10 of these 35 SNPs were described in studies of African or Afro-American populations ( Mechanic et al, 2007 ; Chornokur et al., 2013b ; Nikolić et al, 2014 ; Oh et al, 2017b ; Oussalah et al, 2017 ; Tong et al., 2018 ; Jones et al, 2019 ; Sagna et al, 2019 ; Song et al, 2019 ; Kamiza et al., 2020 ), suggesting that most association studies including these SNPs focused on European and Asian populations. The present results showed that a high number of individuals were homozygous for risk alleles with Native American and African ancestry that may modify the risk of cancer.…”